The zebrafish as a potential model for vaccine and adjuvant development

ABSTRACT

Introduction

Zebrafishes represent a proven model for human diseases and systems biology, exhibiting physiological and genetic similarities and having innate and adaptive immune systems. However, they are underexplored for human vaccinology, vaccine development, and testing. Here we summarize gaps and challenges.

Areas covered

Zebrafish models have four potential applications: 1) Vaccine safety: The past successes in using zebrafishes to test xenobiotics could extend to vaccine and adjuvant formulations for general safety or target organs due to the zebrafish embryos’ optical transparency. 2) Innate immunity: The zebrafish offers refined ways to examine vaccine effects through signaling via Toll-like or NOD-like receptors in zebrafish myeloid cells. 3) Adaptive immunity: Zebrafishes produce IgM, IgD,and two IgZ immunoglobulins, but these are understudied, due to a lack of immunological reagents for challenge studies. 4) Systems vaccinology: Due to the availability of a well-referenced zebrafish genome, transcriptome, proteome, and epigenome, this model offers potential here.

Expert Opinion

It remains unproven whether zebrafishes can be employed for testing and developing human vaccines. We are still at the hypothesis-generating stage, although it is possible to begin outlining experiments for this purpose. Through transgenic manipulation, zebrafish models could offer new paths for shaping animal models and systems vaccinology.

KEYWORDS:

• Danio rerio
• zebrafishes
• immunogenicity
• pandemic threats
• coronavirus
• teleost
• vaccinology
• vaccine safety

Article highlights

• The zebrafish represents an innovative model for the study of systems biology and other modern frameworks in biomedicine, but so far this model has been underexplored for human vaccine development and testing.

• The zebrafishes exhibit significant similarity to the human genome – approximately 70% of human genes have a zebrafish equivalent – as well as major components of mammalian innate and adaptive immune systems, with the added advantage of suitability for high-density animal housing and potentially addressing the principles of replacement, reduction, and refinement (3Rs).

• For vaccine safety, the zebrafish could be adapted to examine the effects of vaccines and adjuvants on organ safety due to the optical transparency of the zebrafish’s embryonic and larval stages.

• For innate immunity, the zebrafish offers refined ways to look at adjuvants, adjuvant systems, or adjuvanted vaccines on toll-like receptors (TLRs) or NOD-like receptors (NLRs) on myeloid cells or their OMICs. This could allow for rationally selecting existing adjuvants or new synthetic adjuvants through immuno-engineering.

• For studying adaptive immunity, the zebrafish, like other teleost fish, produces IgM, IgD, and two types of IgZ immunoglobulins. This aspect of zebrafish immunology is not as well studied due to less availability of immunological reagents and kits.

• Through a well-referenced zebrafish genome, transcriptome, proteome, metabolome, and epigenome (collectively known as ‘OMICs’), together with transgenic manipulation, the availability of genetic knock-outs and knock-downs, and possibly artificial intelligence applied to zebrafish bioinformatics, these teleosts have the potential for the study of systems vaccinology.

Declaration of interest

The team of scientists at Texas Children’s Hospital Center for Vaccine Development including its co-directors, Professors P Hotez and M E Bottazzi, are co-inventors of neglected tropical disease vaccines and a COVID-19 recombinant protein vaccine technology owned by Baylor College of Medicine (BCM). The COVID-19 vaccine technology was recently licensed by BCM non-exclusively and with no patent restrictions to several companies committed to advancing vaccines for low- and middle-income countries. The co-inventors have no involvement in license negotiations conducted by BCM. Similar to other research universities, a long-standing BCM policy provides its faculty and staff, who make discoveries that result in a commercial license, a share of any royalty income. Any such distribution will be undertaken following BCM policy. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

PJ Hotez wrote the first draft of the article. All authors contributed to the conception and design of the review article and interpreting the relevant literature and have been involved in writing the review article or revising it for intellectual content.

Acknowledgments

The authors would like to acknowledge the thoughts and advice of the following individuals who responded to email queries regarding the potential for zebrafishes to serve as models for vaccine development and testing: Dr. Jeff Yoder, North Carolina State University, College of Veterinary Medicine, Dr. David Tobin, Duke University School of Medicine, Dr. Lalita Ramakrishnan, Cambridge University.

Disclaimers

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of other entities.

Additional information

Funding

This paper was not funded.